Glycol ethers represent a group of widely used chemical in industry and in consumer products. Glycol ethers are readily absorbed through the inhalation, dermal and oral routes, therefore, human occupational and household exposure to glycol ethers can be substantial. The lower alkane members of this group are highly toxic; particularly, 2-methoxyethanol (EGME) which has been reported to cause CNS toxicity in exposed humans, and hematological and testicular toxicity in exposed animals. EGME also causes chromosome damage in bone marrow cells and dominant lethality in offspring of exposed mice and rats. The mutagenic effects were observed after low but not after high doses. Genotoxic effects after multiple low dose exposures, analogous to human exposure conditions, have not been investigated. Proposed research will examine two hypothesis: 1) that for highly toxic agents, like EGME, multiple low dose exposures are more mutagenic and less toxic than single or multiple high doses; 2) EGME metabolic activation in situ and binding are responsible for its target organ genotoxicity. Specific aims are to systematically evaluate the cytogenetic effect in somatic and in male germinal cells of mice after single low dose exposure to a wide dose range of EGME. Subsequently, the cumulative and dose-rate-effects will be analyzed by exposing mice to fractionated and multiple doses (subacute and subchronic) of EGME. Transmissible genetic effects will be evaluated by the spermatocyte assay and extended by the dominant lethal assay. Differential genotoxic effects of EGME in somatic and in male germinal cells will be evaluated. The germinal cell data will be used to estimate the genetic risk in population exposed to EGME. Anther aim is to probe the mechanism of EGME toxicity by determining target tissue activities of the enzymes (alcohol and aldehyde dehydrogenase) which convert EGME to reactive metabolites. Potential induction of these enzymes by repeated EGME exposure will be examined. Labeled EGME will be used to determine if target organ effects are associated with preferential distribution/binding of the toxin. This proposed study will provide important information regarding the genetic hazard from low dose exposure to EGME and the mechanism for target organ genotoxicity.